2Longevity Institute and Department of Biological Sciences; School of Gerontology; University of Southern California; Los Angeles, CA USA

*Correspondence to: Valter D. Longo, Email: vlongo@usc.edu

Yeast is widely regarded as one of the most valuable model systems to study aging and particularly the genetics of aging. Researchers have established two different methods to study yeast aging known as the replicative lifespan (RLS) and the chronological lifespan (CLS). These have led to the identification of many mammalian genes that affect aging suggesting that they will continue to shed light on the fundamental biology of aging. In spite of the clear differences underpinning the mitotic cellular potential (RLS) and the survival in the non-dividing mode (CLS), the two models are clearly regulated by partly overlapping regulatory mechanism. This idea is supported by the observation that chronologically aged diploid cells show decreased replicative lifespan proportional to the duration of the chronological aging.1 Even though this is generally agreed to be true, very few attempts have been made to integrate both models in a comprehensive manner. Furthermore, while mutations that affect Ras-cAMP-PKA or TOR/Sch9 signaling increase both the replicative and chronological lifespan, other genes appear to affect lifespan in only one of the two models indicating that partially distinct mechanisms affect the two aging processes.

In August 15 issue of Cell Cycle, Matt Kaeberlein and coworkers2 present very interesting data, which help to fill the gap between the two aging model systems. They confirm1 that diploid chronologically aged yeast cells have a reduced replicative lifespan with respect to chronologically younger cells and show that pH and media composition (YPD or SDC) during the chronological aging phase, play a role in this phenomenon. S. cerevisiae, grown in 2% dextrose and excess amino acids, the media used in most chronological lifespan experiments, produces both ethanol and acetic acid as a normal end product of alcoholic fermentation which is accompanied by a drop in media pH to below 4.4 It has also been demonstrated that the level of protein oxidation may be acetic acid-dependent and not simply pH-dependent.5 In addition, intracellular acidification increases Ras signaling as well as ROS production,6,7 linking acidification to nutrient signaling pathways. These results are paralleled by the observations that mammalian tumor cells, maintained in stationary culture, lose viability by lactate media acidification8 indicating that acidification may have a conserved role in accelerating cellular aging. Together with previous studies, the work by Murakami et al. support two important conclusions: (1) acidification accelerates chronological aging, an effect which may be conserved in higher eukaryotes and that acetic acid does not simply function as a molecule with a toxic and “private” effect but as a carbon source that causes an expected pro-aging effect. In agreement with this conclusion are the consistent effects on lifespan of mutations in the Tor/S6K and Ras/cAMP/PKA, which are observed independently of the presence or absence of acetic acid in the media or acidification; (2) chronological aging also promotes replicative aging underlining the existence of only one major aging process in yeast which can be measured by two different methods.3,4

Thus, acetic acid is likely to accelerate aging by preventing entry into a calorie restricted-like state, but similar pro-aging effects are also true for any carbon source including glucose and ethanol as suggested by previous studies.4 Under physiological conditions, it is unlikely that acetic acid plays a central role in acidification and, thus, acetic acid and acidification should not be viewed as necessarily connected but as separate factors that can accelerate aging.5,10

Interestingly, the authors also find asymmetric segregation of chronologically aged cellular components. Asymmetric inheritance during cell division is of general interest and has long been debated. In budding yeast, buds show the same mitotic potential with no respect to the mother cell age. It has also been demonstrated that carbonylated proteins, DNA circles and old mitochondrial aconitase remain confined to the aging mother cell. Mechanisms implying the involvement of septin, nuclear pore segregation and the involvement of Sir2 have been postulated.9 The authors here speculate that asymmetric inheritance during mitotic cell division may have had an evolutionary role since yeast cells cycle between dividing and non-dividing states and the damage accumulated in the non-dividing mode may be altruistically confined to mother cells when the cell starts dividing again.

In summary, this is a valuable study solidifying the overlap between yeast replicative and chronological aging and providing strong evidence for the role of acetic acid and acidification as accelerators of the yeast aging process, which may be more relevant to mammalian aging than expected.